CN103059048A - Method for preparing cefpiramide acid - Google Patents
Method for preparing cefpiramide acid Download PDFInfo
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- CN103059048A CN103059048A CN2011103223578A CN201110322357A CN103059048A CN 103059048 A CN103059048 A CN 103059048A CN 2011103223578 A CN2011103223578 A CN 2011103223578A CN 201110322357 A CN201110322357 A CN 201110322357A CN 103059048 A CN103059048 A CN 103059048A
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Abstract
The invention provides a method for preparing cefpiramide acid. The method provided by the invention adopts (6R,R7)-3-[(1-methyl-1H-tetrazolyl-5-yl)thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]octyl-2-alkenyl-2-carboxylic acid as a trimethylchlorosilicyl protective agent. The method provided by the invention is simple to operate, obviously enhances the product purity and yield, and can easily implement industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to a kind of method for preparing Cefpiramide Acid.
Background technology
Cefpiramide (Cefpiramide) belongs to the Third generation Cephalosporins antimicrobial drug, by SUMITOMO CHEMICAL Pharmaceutical Co., Ltd and Yamanouchi Pharmaceutical Co., Ltd's joint research and development exploitation, and in 1985 in Japanese Initial Public Offering, recorded by the U.S. and Japanese Pharmacopoeia, be applicable to responsive G+ and G-bacterium such as intestinal bacteria, proteus, Klebsiella Pneumoniae, Pseudomonas aeruginosa, hemophilus influenza, streptococcus pneumoniae, pneumonia due to the staphylococcus aureus, acute bronchitis, acute episode of chronic bronchitis, the bronchiectasis accompanying infection, pyelonephritis, the wing skin is scorching, cholecystitis, cholangitis, peritonitis, the infectious diseases such as adnexitis.
The chemistry of Cefpiramide Acid is called (6R, 7R)-7-[(2R)-(4-hydroxyl-6-methyl-3-pyridine) formamido--2-(the light basic phenyl of 4-) acetamido]-3-[(1-methyl isophthalic acid H tetrazolium-5-yl) thiomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, its structural formula is as follows:
Cefpiramide Acid can be considered as by side chain (R2)-2-[(4-hydroxyl-6-methyl-3-pyridine) formamido-]-2-(4-hydroxy phenyl) acetic acid (A-B part; be called for short side-chain acid) and parent nucleus (6R; R7)-and 3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (C-D part; be called for short 7-ATCA) form, present existing Cefpiramide Acid preparation method comprises the carboxyl of side-chain acid and the amino of parent nucleus is formed by the acylation reaction condensation under certain condition.But; the processing of 7-ATCA normally adds trimethylchlorosilane and triethylamine and carries out the protective reaction of trimethylchloro-silicane alkyl in this reaction in methylene dichloride; reaction solution after the protection is suspension, and inhomogeneous reaction can not guarantee the fully degree of protective reaction, affects easily the effect of subsequent reactions.In addition, reaction also needs after finishing reaction solution changed in the methylene dichloride water mixed liquid and is hydrolyzed crystallization, need to stir soon, and easy fuel-displaced conglomeration is not suitable for scale operation.
Therefore, still be necessary to improve the synthetic method of Cefpiramide Acid.
Summary of the invention
Therefore, the purpose of this invention is to provide a kind of improved method for preparing Cefpiramide Acid.
The objective of the invention is to be achieved through the following technical solutions.The invention provides a kind of method for preparing Cefpiramide Acid; described method adopts N; the two trimethylsilyl ethanamides of O-are as reactant (6R, 7R)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-the trimethylchloro-silicane alkyl protective material of 7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.
In a preferred embodiment, method provided by the invention may further comprise the steps:
1) with (6R, 7R)-and 3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (7-ATCA) adds in the methylene dichloride and stirs, add again N, the two trimethylsilyl ethanamides (BSA) of O-carry out the protective reaction of trimethylchloro-silicane alkyl, and stirring reaction is to molten clear;
2) with D-α-(6-methyl-4-hydroxy nicotinoyl amine)-4-hydroxyphenyl acetic acid (HOPG-NAD, 7 side chains of amine,) be dissolved in N, in the dinethylformamide (DMF), be cooled to-60～-50 ℃, drip Vinyl chloroformate (ECF) and N-methylmorpholine (N-MMP) and react, the reaction times is for example 1 hour;
3) with step 1) gained solution drops to step 2) in the gained solution, in-60～-50 ℃ of reactions 4-6 hour, preferably, in-55 ℃ of reactions 4 hours;
4) with step 3) gained solution is warming up to 0～10 ℃, the agitation and dropping sodium hydrogen carbonate solution, hydrolysis is (to slough the protecting group of Cefpiramide Acid; and the reaction product salify is soluble in water; make things convenient for the back to extract), filter the filtrate standing demix; organic addition water extraction secondary; merge the gained water, add acetone, transfer pH to 1～2; crystallization, and get final product.
Preferably, described step 1) (6R in, 7R)-and 3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and methylene dichloride, N, weightmeasurement ratio (the g: ml: be 3～4: 15～16 ml): 5～6 of the two trimethylsilyl ethanamides of O-, more preferably, three's consumption is respectively 38 grams, 160 milliliters, 57 milliliters.
Preferably, described step 1) (the 6R in, 7R)-and 3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid prepares by the following method: 7-amino-cephalosporanic acid (7-ACA) and 1-methyl isophthalic acid H-tetrazole-5-mercaptan (MMT) is added in the acetonitrile and stirs, under 28～32 ℃, be added dropwise to again in the catalyzer boron trifluoride acetonitrile complex compound (BC) and react, reaction times is 1～3 hour, preferred 1.5 hours, crystallization, and get final product.
Preferably, described step 1) the crystallization operation that comprises in is as follows: reaction solution is changed over to 0 ℃ water, 5 minutes crystallize outs of stir about, slowly stirred growing the grain 30 minutes, dripping ammoniacal liquor accent pH is 2.4～2.6, growing the grain 2 hours, filter, wash crystalline substance with mixing solutions, water and the acetone of acetonitrile and water successively, drying, and get final product.More preferably, described to wash brilliant solvent as follows successively: mixing solutions, 300 ml waters and 300 milliliters of acetone of 205 milliliters of acetonitriles and 90 ml waters.
Preferably, the consumption of D-α-(6-methyl-4-hydroxy nicotinoyl amine)-4-hydroxyphenyl acetic acid is 36 grams (when being 38 gram with respect to the amount of 7-ATCA in the step 1) described step 2).
Preferably, described step 3) consumption of sodium hydrogen carbonate solution is about 14～15 grams in, and control pH 6～8 gets final product.
Preferably, described step 3) the crystallization operation in is as follows: add acetone at the gained aqueous phase, the amount of acetone is 1 times of water volume, transfers pH to 1～2 (control rate of addition in 0～10 ℃ of lower (such as 10%) hydrochloric acid that drips, transferred pH to 1～2 in about 1 hour), crystallization.
As seen; the method for preparing Cefpiramide Acid provided by the invention; with methylene dichloride as solvent; make (6R; 7R)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (7-ATCA) with (R2)-2-[(4-hydroxyl-6-methyl-3-pyridine) formamido-]-the amidation hydrolysis reaction occurs in 2-(4-hydroxy phenyl) acetic acid (HOPG-NAD-ECF); obtain Cefpiramide Acid; N wherein; the two trimethylsilyl ethanamides (BSA) of O-are as the trimethylchloro-silicane alkyl protective material of 7-ATCA; reaction solution after the protection is the clarification homogeneous phase solution; reaction on the one hand can adequately protect; deprotection after reaction is finished on the other hand is simple to operate; only get final product deprotection by hydrolysis; not only overcome in the prior art reactants dissolved not exclusively or intermediate product do not dissolve the detrimentally affect that causes, and easy control easy and simple to handle.In addition, the inventive method is the equal of the purification process of a hypo acid in crystallization, and products obtained therefrom purity and yield all obviously improve.The concrete synthetic route that relates in the aforesaid method is as follows:
Wherein employed 7-ATCA preferably can carry out substitution reaction to 7-amino-cephalosporanic acid (7-ACA) by 1-methyl isophthalic acid H-tetrazole-5-mercaptan (MMT) and synthesizes, and concrete synthetic route is as follows:
Adopt the 7-ATCA of aforesaid method preparation, not only simple to operate, also further improved the purity of product, its molar yield is also significantly improved, be conducive to the reaction of next step synthetic Cefpiramide Acid.
Embodiment
Referring to specific embodiment the present invention is described.It will be appreciated by those skilled in the art that these embodiment only are used for explanation the present invention, the scope that it does not limit the present invention in any way.
Embodiment 1
Present embodiment provides the method for preparing employed reactant 7-ATCA in the inventive method.
Concrete operations are as follows: add 7-amino-cephalosporanic acid (7-ACA) 90 grams in 1000 milliliters of four-hole bottles, and 1-methyl isophthalic acid H-tetrazole-5-mercaptan (MMT) 42.1 grams, 595 milliliters of acetonitriles stir.Room temperature (such as 20～25 ℃) is added dropwise to 412.5 milliliters in boron trifluoride acetonitrile complex compound (BC), and 28～32 ℃ of temperature controls added afterreaction 1.5 hours, reaction finishes, reaction solution changes in 660 milliliters of purified water that are cooled in advance 0 ℃, and 5 minutes crystallize outs of stir about stirred growing the grain 30 minutes slowly, dripping 10% ammoniacal liquor accent pH is 2.4～2.6, growing the grain 2 hours filters, and uses successively 205 milliliters of acetonitriles+90 ml waters, 300 ml waters, 300 milliliters of acetone are washed crystalline substance.35～40 ℃ of vacuum-dryings get white solid powder 99 grams to moisture＜1%.
HPLC detects purity 98.9%, 208～212 ℃ of fusing points.
The 7-ACA molecular weight is that 272.27,7-ATCA molecular weight is 328.37, and the theoretical weight yield is 328.37/272.27=1.206, and the weight yield of real income product 7-ATCA is 1.1, and molar yield is 0.912.
Comparative Examples 1
This Comparative Examples provides the employing art methods to prepare 7-ATCA.
Concrete operations are as follows: add acetonitrile 650ml in the 2L there-necked flask, cool to-20 ℃, temperature control drips vitriol oil 160ml, add MMT 47g, 7-ACA 100g is warmed up to 30 ℃ naturally, clock reaction 3 hours cools to 10 ℃, adds the hydrochloric acid soln of precooling, temperature control stirred 2 hours below 10 ℃, filtered, flushing acetonitrile 100ml, acetone 300ml, 40 ℃ of dried overnight get white solid powder 110 grams.
HPLC detects purity 98.5%, fusing point mp197～201 ℃.
As calculated, the weight yield of products therefrom 7-ATCA hydrochloride (TACAHCL, molecular weight 362.38) is 1.1, and molar yield only is 0.826.
Embodiment 2
This enforcement provides the method for preparing employed reactant HOPG-NAD-ECF in the inventive method.
Concrete operations are as follows: add N in the 250ml there-necked flask, dinethylformamide (DMF) 180ml, be cooled to below 10 ℃, add D-α-(6-methyl-4-hydroxy nicotinoyl amine)-4-hydroxyphenyl acetic acid (HOPG-NAD) 36g, stir 30min, be cooled to below-60 ℃, 30min drips Vinyl chloroformate (ECF) 20ml, drip off rear dropping N-methylmorpholine (N-MMP) 13ml, drip off and stir 10min, be cooled to-70 ℃ for subsequent use.
Embodiment 3
This enforcement provides the present invention to prepare the method for Cefpiramide Acid.
Concrete operations are as follows: add 7-ATCA 38g in 250 milliliters of there-necked flasks, and methylene dichloride 160ml, stirring at normal temperature is added dropwise to BSA 57ml, and stirring reaction is to molten clear; The gained reaction solution is added dropwise in the made HOPG-NAD-ECF solution of embodiment 2, temperature control-60 ℃, reacted 4 hours, be warming up to 0 ℃, agitation and dropping sodium hydrogen carbonate solution (16.7g sodium bicarbonate+167ml water) hydrolysis is filtered, the filtrate standing demix, organic 440ml that makes an appointment adds water 100ml, extracting twice at every turn, merge the about 360ml of gained water, add acetone 360ml, drip hydrochloric acid and transfer pH=1～2 crystallizatioies, 0～10 ℃ of growing the grain 1 hour, filter, wash crystalline substance with 100ml water, 100ml acetone respectively, 45 ℃ of vacuum-dryings get cefpiramide acid crude 51g.
It is 96% that HPLC detects purity.
Amino acid molecular weight is that 612.63,7-ATCA molecular weight is 328.36, and the theoretical weight yield is 1.87, and the weight yield of real income product Cefpiramide Acid is 1.34, and molar yield is 0.72.
Comparative Examples 2
Comparative Examples provides the employing art methods to prepare Cefpiramide Acid.
Concrete operations are as follows: add methylene dichloride 160ml in the 1L four-hole bottle, be cooled to below 20 ℃, add trimethylchlorosilane (TMCS) 35ml, be cooled to-10 ℃, the TACAHCL 41g that adds Comparative Examples 1 preparation, temperature control drips triethylamine (TEA) 52.5ml and methylene dichloride 50ml less than-5 ℃, drips off and stirs 30min, is cooled to-72 ℃, HOPG-NAD-ECF solution with embodiment 2 preparations changes over to fast, flushing DMF (DMF) 12ml, temperature control-58～-60 ℃ reaction 4h, slowly be warming up to-40 ℃ in 1 hour, reaction finishes reaction solution is changed among 5 ℃ of methylene dichloride 2250ml and the water 750ml, washes DMF 12ml, has turned to stir soon 1h and stir slowly 2h again, filter, use respectively 100ml water, 100ml acetone is washed crystalline substance, and 45 ℃ of vacuum-dryings get cefpiramide acid crude 48.5g.
It is 88% that HPLC detects purity.
As calculated, the weight yield of products therefrom Cefpiramide Acid is 1.18, and molar yield is 0.70.
Claims (6)
1. method for preparing Cefpiramide Acid; it is characterized in that; described method adopts N; the two trimethylsilyl ethanamides of O-are as reactant (6R, 7R)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-the trimethylchloro-silicane alkyl protective material of 7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.
2. method according to claim 1 is characterized in that, said method comprising the steps of:
1) with (6R, 7R)-and 3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in the methylene dichloride, add N, the two trimethylsilyl ethanamides of O-, stirring reaction is to molten clear;
2) D-α-(6-methyl-4-hydroxy nicotinoyl amine)-4-hydroxyphenyl acetic acid is dissolved in the DMF, is cooled to-60～-50 ℃, drip the reaction of Vinyl chloroformate and N-methylmorpholine;
3) with step 1) gained solution is added dropwise to step 2) in the gained solution, in-60～-50 ℃ of reactions 4-6 hour;
4) with step 3) the gained reaction solution is warming up to 0 ℃～10 ℃, and the agitation and dropping sodium hydrogen carbonate solution is transferred pH to 6～8 hydrolysis, filters, the filtrate standing demix, organic addition water extraction secondary merges the gained water, crystallization, and get final product.
3. method according to claim 2, it is characterized in that, described step 1) (6R in, R7)-and 3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and methylene dichloride, N, the weightmeasurement ratio (g: ml: be 3～4: 15～16 ml): 5～6 of the two trimethylsilyl ethanamides of O-.
4. according to claim 2 or 3 described methods, it is characterized in that, described step 1) (6R, the 7R) in-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid prepares by the following method:
7-amino-cephalosporanic acid and 1-methyl isophthalic acid H-tetrazole-5-mercaptan are added in the acetonitrile and dissolve, under 28～32 ℃, be added dropwise to again in the boron trifluoride acetonitrile complex compound and react, crystallization, and get final product.
5. method according to claim 4 is characterized in that, described step 1) in the crystallization operation that comprises as follows:
To change over to 0 ℃ water in reaction solution, 5 minutes crystallize outs of stir about stirred growing the grain 30 minutes slowly, dripped ammoniacal liquor and transferred pH to 2.4～2.6, and growing the grain filters, and washes crystalline substance with mixing solutions, water and the acetone of acetonitrile and water successively, drying, and get final product.
6. each described method in 5 according to claim 1 is characterized in that described step 3) in the crystallization operation as follows:
Add acetone at the gained aqueous phase, in 0～10 ℃ of lower hydrochloric acid accent pH to 1～2, crystallization of dripping.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109438477A (en) * | 2018-11-08 | 2019-03-08 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of Cefpiramide Acid |
| CN109721618A (en) * | 2017-10-30 | 2019-05-07 | 刘力 | Cefpiramide noval chemical compound and combinations thereof and purposes |
| CN111072688A (en) * | 2019-12-30 | 2020-04-28 | 湖北凌晟药业有限公司 | Method for refining cefpiramide acid |
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| CN1594324A (en) * | 2004-07-07 | 2005-03-16 | 广州白云山医药科技发展有限公司 | Process for preparing cefpiramide sodium |
| CN101607965A (en) * | 2008-06-17 | 2009-12-23 | 辅仁药业集团有限公司 | A kind of novel process for preparing Wy-44635 |
| CN101768168A (en) * | 2008-12-30 | 2010-07-07 | 上海新先锋药业有限公司 | Method for synthesizing cephalosporin intermediate |
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2011
- 2011-10-21 CN CN2011103223578A patent/CN103059048A/en active Pending
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| JPS5965094A (en) * | 1982-10-06 | 1984-04-13 | Sumitomo Chem Co Ltd | Preparation of cephalosporin compound |
| CN1594324A (en) * | 2004-07-07 | 2005-03-16 | 广州白云山医药科技发展有限公司 | Process for preparing cefpiramide sodium |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109721618A (en) * | 2017-10-30 | 2019-05-07 | 刘力 | Cefpiramide noval chemical compound and combinations thereof and purposes |
| CN109438477A (en) * | 2018-11-08 | 2019-03-08 | 华北制药河北华民药业有限责任公司 | A kind of refining methd of Cefpiramide Acid |
| CN109438477B (en) * | 2018-11-08 | 2020-04-28 | 华北制药河北华民药业有限责任公司 | Method for refining cefpiramide acid |
| CN111072688A (en) * | 2019-12-30 | 2020-04-28 | 湖北凌晟药业有限公司 | Method for refining cefpiramide acid |
| CN111072688B (en) * | 2019-12-30 | 2021-05-04 | 湖北凌晟药业有限公司 | Method for refining cefpiramide acid |
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Application publication date: 20130424 |